Abstract A021: Reactive osteogenic-niche regulation of endocrine resistance in prostate cancer bone metastases: Role of tenascin-C induced metabolic shift in regulating therapeutic resistance in prostate cancer
Authors: Rintu T. Thomas, David R. Rowley
Journal: Cancer Research (2023)

Abstract Background: The main objective of the study is to investigate the regulatory role of reactive osteogenic niche in evolution of therapeutic resistance in prostate cancer bone metastases. Prostate cancer that metastasize to the bone develop into an androgen insensitive/therapeutic resistant state known as metastatic castration resistance prostate cancer (mCRPC). In bone, prostate cancer cells spatially associate with reactive osteogenic niche typified with elevated expression of the repair-associated, extracellular matrix protein- tenascin-C. Our recent finding show that tenascin-C regulates splicing and post-translational stability of therapeutic resistant- androgen receptor splice variant- AR-V7. Expression of AR-V7 and induction of de novo lipogenesis is observed to co-evolve in mCRPC. In this study, we evaluated the role of tenascin-C in regulating de novo lipogenesis in prostate cancer cells and its association with AR-V7 expression. Methods: Immunofluorescence imaging were conducted to assess spatial localization of lipids using BODIPY 493/503 in prostate cancer cells interacting with tenascin-C- expressing osteogenic cells-preosteoblast using a novel heterotypic 3D organoid model. Prostate cancer cells cultured on tenascin-C were subjected to lipidomic analysis using LC-MS for characterization of tenascin-C induced lipid accumulation. RT-qPCR and Western blotting were conducted to evaluate differential regulation of enzymes involved in de novo lipogenesis by tenascin-C. siRNA and small molecular inhibitors were utilized to evaluate molecular association between tenascin-C, enzymes regulating de novo lipogenesis, and AR-V7 in prostate cancer cells. Results: Imaging of heterotypic organoids revealed lipid accumulation in prostate cancer cells interacting with tenascin-C expressing preosteoblasts. Lipidomic analysis confirmed tenascin-C induced enrichment of neutral lipids such as di and triglycerides in prostate cancer cells, a novel finding. Tenascin-C also induced expression of enzymes regulating de novo lipogenesis such as acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) in prostate cancer cells (p˂ 0.01). Assessment of clinical transcriptomic datasets confirm significant upregulation of both tenascin-C and specifically ACACA in prostate cancer bone metastases compared to other visceral metastatic sites (p=1E-10, p=1E-7). Importantly, we observed tenascin-C induced upregulation of ACACA and FASN expression in prostate cancer cells was impeded by AR-V7 knockdown. Conversely, inhibition of ACACA activity (CP-640186 at 0.5 uM) also suppressed AR-V7 protein expression in prostate cancer cells. Conclusions: In summary, this study suggests a complex functional association between a reactive osteogenic niche component -tenascin-C, and AR-V7 expression with de novo lipogenesis in prostate cancer cells. Targeting to uncouple the tenascin-C regulated de novo lipogenesis in prostate cancer cells may be a promising therapeutic strategy to prevent evolution of AR-V7 expression and development of mCRPC. Citation Format: Rintu T. Thomas, David R. Rowley. Reactive osteogenic-niche regulation of endocrine resistance in prostate cancer bone metastases: Role of tenascin-C induced metabolic shift in regulating therapeutic resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A021.